The peripheral T cell pool in healthy individuals is maintained by both thymic output and peripheral homeostasis. The thymus exports newly generated T cells throughout the lifetime of the individual. These cells, called recent thymic emigrants or RTEs, predominate in the neonatal period and in the adult, are crucial for maintaining T cell diversity and in reconstituting the naive T cell pool following lymphodepletion through infection or therapeutic intervention. Using a mouse model system in which RTEs can be distinguished from the bulk of peripheral T cells, it is now clear that T cells continue to mature for 2-3 weeks after thymic egress. Activated CD4 and CD8 RTEs exhibit diminished proliferation, decreased cytokine production, and altered surface antigen phenotype compared to similarly treated mature T cells. This distinct functional profile lasts well after RTEs have entered the mature peripheral T cell pool. Proposed experiments encompass the following specific aims: Specific Aim 1: To determine whether CD4 RTEs show a bias against the Th1 and toward theTh2 lineage in vivo. These experiments will determine whether RTEs mount deficient Th1 responses and enhanced Th2 responses in vivo. Specific Aim 2: To investigate whether the epigenetic control of cytokine loci in RTEs is distinct from that in mature naive T cells. These experiments will assess the plasticity of lineage-committed CD4 RTEs and will investigate chromatin modifications at the Th2, Il2, and Ifng loci of naive and polarized CD4 RTEs and at the Il2 and Ifng loci of naive and activated CD8 RTEs, in an effort to understand the mechanism behind the heritable changes in cytokine expression that distinguish RTEs from mature T cells. Specific Aim 3: To analyze the comparative strength of TCR signal transduction in RTEs and mature naive T cells. These experiments will investigate the events downstream of the TCR leading to dampened RTE responses, the expression of transcription factors that regulate anergy induction and memory/effector cell fate decisions, and the impact of ligand affinity and antigen persistence on RTE function. The focus of these experiments is to understand the relationship between RTE functional traits and anergy and to probe the manner in which RTEs interpret environmental cues that is distinct from their mature counterparts. The overall goal of these studies is to understand the biology of RTEs, a key but under-studied population of peripheral T cells. PUBLIC HEALTH RELEVANCE: The steady export of newly generated T cells (or recent thymic emigrants) is required to maintain the diversity of the T cell compartment throughout life. Recent thymic emigrants make up the bulk of the peripheral T cell pool in neonates, and are required to reconstitute the depleted naive T cell pool in adults. Thus, understanding the biology of recent thymic emigrants is crucial to predicting immune responses in neonates and in adults recovering from lymphodepleting viral infections or therapeutic interventions.